Infection with the protozoan parasite Leishmania major causes significant morbidity in many parts of the world. The mouse model of L. major infection has been considered the paradigm to study polarized Th1/Th2 cytokine responses in vivo, with IL-4-driven Th2 responses as a determinant of susceptibility to L. major infection. Contrary to this well-established model, in genetically pure BALB/c mice deficient for IL-4 receptor alpha chain (IL-4Ralpha-/-), infection with L. major sub-strain LV39 causes highly progressive disease; similar to susceptible BALB/c mice, while the L. major sub-strain IR173 is highly controlled. These results suggest that factors other than IL-4 are capable of suppressing IFNgamma activated killing of intracellular L. major parasites. IL- 10 has been identified as the factor, which causes susceptibility to L. major LV39 in IL-4Ralpha-/- mice. In IL-4Ralpha-/- mice treated with neutralizing anti-IL-10 receptor antibody and in BALB/c mice genetically deficient for both IL-4Ralpha and IL-10, the disease to L. major LV39 infection was reversed to a healing phenotype. This proposal exploits the disparate outcomes of L. major LV39 and IR173 infections to assess cytokine regulation, the role of IL-10-secreting Treg cells, the roles of macrophages and dendritic cells in directing T cell immune responses to L. major infection, and the efficacy and mechanisms of protection by L. major vaccines. The long-term goal of these studies is to identify the cellular processes and antigens involved in L. major immune escape mechanisms, which are fully revealed in the absence of IL-4/IL- 13 signaling. These studies have implications for the development of therapies and vaccines directed toward Leishmania infections as well as the mechanisms that regulate Th1/Th2 cytokine development in vivo.